Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness

作者：Davidson Alice E; Cheong Sek Shir; Hysi Pirro G; Venturini Cristina; Plagnol Vincent; Ruddle Jonathan B; Ali Hala; Carnt Nicole; Gardner Jessica C; Hassan Hala; Gade Else; Kearns Lisa; Jelsig Anne Marie; Restori Marie; Webb Tom R; Laws David; Cosgrove Michael; Hertz Jens M; Russell Eggitt Isabelle; Pilz Daniela T; Hammond Christopher J; Tuft Stephen J; Hardcastle Alison J^*

来源：PLos One, 2014, 9(8): e104163.

DOI：10.1371/journal.pone.0104163

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhauser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p=6.81x10(-6)) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.

• 出版日期2014-8-5
• 单位河北医科大学